Discussion

The prevalence of AD is the highest in the infant age group and the incidence in infants continued to increase during recent years (12, 78). Because of this high prevalence and the substantial impact that the disease has on the QoL of both patients and caregivers, safe and effective treatment options for infants with AD are needed (2, 4, 42). Treatment should focus on lifelong management, providing rapid symptom relief to reduce the significant socioeconomic burden as early as possible (44). Additionally, restoration of the skin barrier by early treatment may prevent AD worsening into more severe conditions, its persistence into later life, and the progression of the atopic march (13, 24, 38, 79). Despite the well-known rationale to initiate treatment of AD during infancy, there is still an unmet medical need of alternative treatment options to TCS, which remain the mainstay of treatment in infants with AD (14). TCIs are one of these alternative treatment options, overcoming most limitations of TCS, including poor adherence due to corticophobia and rebound flares upon discontinuation (16, 46, 53). Additionally, TCIs are steroid-sparing reducing the risk of chronic exposure to TCS which may result in skin atrophy and subsequently increased percutaneous absorption of steroids in the infant, especially when used in sensitive skin areas (14, 22, 47, 49, 58). All studies, except for one, evaluating safety and efficacy of TCIs for the infant indication have been conducted with pimecrolimus. Based on the available evidence, the efficacy of pimecrolimus for the treatment of infants with AD has never been questioned and was also found to be comparable to the use of TCS in the 5-year PETITE study (58). Nevertheless, pimecrolimus is in most countries only approved as second-line treatment for short-term use in children with AD above the age of 2 years due to initial concerns about long-term safety. Safety concerns were the result from preclinical carcinogenicity studies demonstrating that systemic exposure of animals to immunosuppressant doses of TCIs resulted in malignancies (17, 80). The preclinical safety concerns were reinforced by cases of lymphoma and skin cancer in patients who were treated systemically with calcineurin inhibitors (cyclosporine and tacrolimus) after whole organ transplantation. These findings ultimately led to the inclusion of a black-box warning in the US and the second-line use of TCIs in Europe which was based on a theoretical rather than a proven risk of malignancy (17, 80). However, systemic exposure to pimecrolimus upon topical application is negligible, even in infants who have the greatest body surface area-to-weight ratio (61-63, 65). Accordingly, epidemiological studies failed to find a causal relationship between use of pimecrolimus and malignancies in patients with AD (68-70, 72, 74). However, patients included these studies often only had short or unknown exposure times to pimecrolimus without focusing on the pediatric population. Therefore, the 5-year PETITE study was designed to assess the risk on immunosuppression in infants using pimecrolimus for a median of 224.5 days (58). Based on the results from the PETITE study, topical pimecrolimus had no effect on the developing immune system and no malignancies were reported in infants treated with pimecrolimus (58). To refute the argument that the follow-up time of the PETITE study was insufficient to examine the association between pimecrolimus and malignancies, the PEER was initiated in 2004, albeit not in infants but in pediatric patients above the age of 2 years (71). The most recent results from the PEER did not report any cases of malignancies that could be related to immunosuppression and provided the ultimate evidence that use of topical pimecrolimus is not associated with an increased cancer risk ((71) and Meda data on file). Another registry similarly evaluated the long-term safety of tacrolimus ointment in children with AD. This registry confirmed that there is currently no evidence supportive of an increased long-term cancer risk in children with AD who had been treated with TCIs (81). Due to the extensive amount of studies that have been conducted to evaluate the safety of pimecrolimus for the treatment of AD in the pediatric population, data on the long-term use of pimecrolimus are now surpassing these collected for mid- to high-potency TCS (82). After nearly 20 years of clinical experience, the Expert Panel concluded accordingly that it is no longer appropriate to restrict the use of pimecrolimus to children above the age of 2 years. This is reflected particularly by the recent approval of pimecrolimus for treatment of infants with AD and the removal of the black-box warning in Canada in 2019 (83). Additionally, the recently published consensus-based European guidelines recommend long-term use of TCIs for sensitive skin areas in the pediatric population (14). Based on the available evidence and expert opinion, the European Expert Panel concludes that treatment of AD should be initiated as early as infancy, and topical pimecrolimus is a safe and effective steroid-sparing treatment option for both short and long-term use, that should no longer be withheld from infants aged 3 months and above.